This proposes a comprehensive 5-year physician scientist career development plan for Dr. Talia H. Swartz. Dr. Swartz completed a PhD in bacterial membrane bioenergetics, MD, and Residency in Internal Medicine and Fellowship in Infectious Diseases all at the Icahn School of Medicine at Mount Sinai. She has been exploring the role of purinergic signaling in HIV disease and has demonstrated that P2X receptors specifically are required for HIV viral membrane fusion. The application builds on Dr. Swartz's preliminary data supporting a key role for purinergic receptors in HIV entry and is structured to transition Dr. Swartz from trainee to independent investigator by leveraging intellectual and material resources at the Icahn School of Medicine at Mount Sinai. Dr. Benjamin Chen has mentored successful trainees and will guide Dr. Swartz throughout her training. Dr. Chen is an established investigator and recognized leader in HIV transmission. An advisory committee composed of highly regarded principal investigators in HIV research will provide additional guidance. Dr. Swartz's career development plan is comprehensive, including frequent meetings, specific relevant coursework, and departmental support centered on mentoring early career investigators. She will attend seminars and national conferences where she will continue to present her research, establish collaborations, and learn of recent advances in his field. Dr. Swartz's research utilizes state-of-the-art molecular and imaging methods to advance understanding of the role of purinergic signaling in HIV-1 infection. She proposes to study the mechanism of purinergic receptor signaling in HIV-1 infection. Purinergic receptors detect extracellular nucleotide that is released during inflammation. Dr. Swartz's preliminary experiments have demonstrated that P2X receptors are required for HIV-1 entry at the level of viral membrane fusion. In the first specific aim, experiments will be conducted to determine which of the three P2X receptors expressed on lymphocytes, P2X1, P2X4, and P2X7, is required for HIV entry using pharmacologic and genetic approaches. The second aim will determine whether HIV can directly activate the receptor. The third aim will address the role of purinergic signaling in inflammation using an ex vivo tonsil model that will build upon preliminary evidence that a P2X7 inhibitor reduces HIV productive infection. Inflammatory biomarkers will be tested to determine whether purinergic inhibition reduces levels of soluble pro-inflammatory cytokine production. Dr. Swartz has a successful research background with eight peer-reviewed publications, four of which are first author and a series of highly cited chapters. The preliminary data have been published in a manuscript this year and with results of a second manuscript with anticipated publication by the end of this year. The Icahn School of Medicine at Mount Sinai has demonstrated commitment to Dr. Swartz's career, with a 75% protected faculty position to conduct her research. Her goal is to develop a successful career as an independent physician scientist in defining key therapeutic agents in the treatment of HIV infection and inflammation.